The long latency of prostate cancer (PCa) provides a window of opportunity for chemoprevention strategies. Most such strategies are focused on controling and/or reversing the mechanisms involved in neoplastic transformation and cancer progression. It is well accepted that, during development and progression, tumor cells evade the patient's defense system. In this regard, natural killer (NK) cells are cellular effectors of the innate immune system and are required for activation of the host defense system and for destruction of tumor cells. In PCa patients, however, the function of NK cells and their numbers are often compromised and/or depleted. Therefore, enhancing the function of NK cells by immunomodulatory compounds is a promising approach for PCa prevention. Recently, we demonstrated the immunomodulatory effects of andrographolide (AG), a natural compound isolated from Andrographis paniculata (AP), on NK cells and have established its antitumor effects in mice bearing PCa PTEN syngeneic tumors. Our preliminary results provide a rationale to investigate the function of AG in potentiating NK cells, which can act to eliminate PCa cells. Based on these encouraging preliminary data, we hypothesize that AG inhibits PCa growth by potentiating the anti-tumor activity of NK cells, thus offering an innovative, immune-based chemopreventive strategy for PCa. To test this hypothesis, we propose two specific aims. The first aim will use mouse models to determine the potential of AG in boosting NK cell activity against PCa. This will be achieved by establishing an interrelationship between the in vivo effects of AG through NK cel mobilization and cytotoxic activities and the effectiveness of AG in adaptive T cell responses through modulation of cytokine production by NK cells. In the second aim, we will establish the effects of AG on development, proliferation/survival, and cytotoxic function of NK cells. These studies, which will determine the effectiveness of AG in PCa chemoprevention achieved through boosting NK cell function, make the proposal clinically relevant and highly translational.